Long acting GI and esophageal protectant

ABSTRACT

A bioadherent, orally ingestible system, which comprises: a water-in-oil emulsion system having at least two phases, one phase comprises from about 75% to about 99% by volume of an internal hydrophylic phase and the other phase comprises from about 25% to about 1% by volume of an external hydrophobic phase, wherein the external hydrophobic phase comprises two components, one component being about 3% to about 97% by volume of the hydrophobic phase of a hydrophobic oil and the other being about 97% to about 3% of an emulsifier having a HLB value less than about 10.

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.08/432,805, filed May 2, 1995, U.S. Pat. No. 5,670,163, which is aContinuation-In-Part application of U.S. patent application Ser. No.08/262,254, filed Jun. 20, 1994, now U.S. Pat. No. 5,554,379, the entirecontents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to stable water-in-oil emulsions that are usableas bioadherent, ingestible systems. The systems are designed to coat andadhere to the oral cavity, epithelial and mucosal membranes of theesophagus and gastrointestinal (GI) tract for extended periods of time.The purpose of the coating is to protect the mouth tissue and membranesof the esophagus and GI tract against gastric fluid, and enzyme attackwhile promoting healing caused by ulcers, esophagitis, and so forth andto release active drug over a controlled release rate. Confectionery andchewing gum compositions containing the emulsions are also described.

2. Description of the Prior Art

Although a need for water-in-oil emulsions having a high water oraqueous phase content has long existed for use in pharmaceuticals,cosmetic and toiletry preparations, such as night creams or barriercreams, moisturizing creams and lotions, it has been difficult toprovide such emulsion where the aqueous phase exceeds 45% to 55% on aweight to weight basis. Although many benefits are to be derived fromproviding a high water content in a water-in-oil emulsion system forcosmetic applications in particular, formulators have not heretoforebeen able to add more than about 50% water to the emulsion withoutseriously affecting the shelf life stability of the preparation. It isto be appreciated in this respect that because of the time delay thatoccurs between formulation of a product and commercial sale, it isundesirable to employ an emulsion which will break in a short period oftime, particularly when exposed to temperature extremes that areencountered during transportation and warehouse storage. Althoughstability under normal climatic conditions is an asset, at the veryminimum the emulsion system should be able to withstand temperatures onthe order of 43° C. (110° F.) for at least six months without breaking.

Water-in-oil emulsions are used in barrier preparations orpore-occluding products to provide a thin oleaginous layer over theareas of the user's skin to which the composition is applied. Increasingthe amount of hydrophylic inner phase in the emulsion decreases the oilyfeel of the material without deleteriously effecting the overall utilityof the formulation. Such formulations have greater customer appealbecause the higher hydrophylic content enhances the evaporative andthereby cooling effect of the cream or lotion upon application. Productsformulated from these emulsion systems are described in U.S. Pat. No.4,385,049 to Robert C. Cuca.

The use of water-in-oil emulsions as a liquid or semi-liquid system fororal use have not been successful. U.S. Pat. No. 2,948,686 to Gianladisdescribes water-in-oil emulsions but the patentee was not able toincorporate more than about 52% water in his emulsion system.

The present invention overcomes these deficiencies by preparing anorally useable and stable emulsion or suspension having at least 75% ofan internal hydrophylic phase with a multifunctional hydrophobicexternal phase containing an oil and mixtures of emulsifiers in highconcentrations. Such systems enable the inventive formulation, whentaken orally to coat and protect the oral cavity and membranes of theesophagus and/or GI tract against high acidity, enzyme degradation andreflux conditions while enabling an active drug to be released from theformulation over controlled rates of release.

SUMMARY OF THE INVENTION

This invention relates to the preparation of a bioadherent, orallyingestible system, which comprises: a water-in-oil emulsion systemhaving at least two phases, one phase comprises from about 75 to about99% by volume of an internal hydrophylic phase and the other phasecomprises from about 25% to about 1% by volume of an externalhydrophobic phase, wherein the external hydrophobic phase is composed ofat least two components, one component being-about 3 to about 97% of ahydrophobic oil and the other being about 97% to about 3% of anemulsifier having a HLB value less than about 10.

In a preferred embodiment the hydrophylic phase contains an activepharmaceutical material which is water-soluble.

In another preferred embodiment water-insoluble active pharmaceuticalmaterials are used in the hydrophobic phase. Additional preferredembodiments involve selecting the hydrophylic phase from water,glycerine, sorbitol solutions, sugar syrups, polymer solutions andmixtures thereof. In contrast, the hydrophobic oil is selected from thegroup consisting of mineral oil, natural or synthetic vegetable oil,long chain fatty acids and alcohols of straight chain alkyls having from12 to 32 carbon atoms, waxes and mixtures thereof.

The emulsions of this invention also contain emulsifiers. Preferably,the emulsifiers are soluble in the hydrophobic (lipoidal) or externalphase. Suitable emulsifiers are those oil miscible surface activecompounds which are acceptable for use in foods, pharmaceuticals, and/orcosmetics Examples of such emulsifiers are low molecular weightpolyglycerols which have been esterified with fatty acids or fatty acidesters, or mono and diglyceride mixtures alone or with the addition ofmetallic soaps, such as, aluminum stearate. The metallic soaps appear toimprove the characteristics of some of the emulsions. Additionalemulsifiers may be present in the hydrophobic phase and are selectedfrom the group consisting of sorbitan esters, polyglycerol esters offatty acids, glycerol esters of fatty acids, 1 to 5 mole ethoxylates offatty acids or esters, saccharides derivatives and mixtures thereof.

In a further embodiment of the invention, a method is provided fortreating an esophageal or GI tract disorder, or for providing for theabsorption of an active material for a systemic effect in a human oranimal, which comprises administering to the oral cavity atherapeutically effective amount of a bioadherent, orally ingestiblesystem, which comprises: a water-in-oil system having at least twophases, one phase comprises from about 75% to about 99% by volume of aninternal hydrophylic phase the other phase comprises from about 25% toabout 1% by volume of an external hydrophobic phase, and wherein theexternal hydrophobic phase is comprised of two components, one componentbeing about 3% to about 97% by volume of the hydrophobic phase of ahydrophobic oil and the other being about 97% to about 3% of anemulsifier having a HLB value less than about 10.

In a further embodiment, a chewing gum composition is provided fordelivering the emulsions of this invention to the oral cavity whichcomprises

a) a gum base in an amount sufficient to form a chewing gum composition;

b) effective amounts of chewing gum additives to soften the gum base;and

c) an effective amount of an active pharmaceutical composition dispersedwithin a water-in-oil emulsion system having at least to phases, onephase comprises from about 75 to about 99% by volume of an internalhydrophylic phase and the other phase comprises from about 25% to about1% by volume of an external hydrophobic phase, wherein the externalhydrophobic phase is comprised of two components, one component beingabout 3 to about 97% of a hydrophobic oil and the other being about 97%to about 3% of an emulsifier having a HLB value less than 10.

In another embodiment, a confectionery composition is provided fordelivering the emulsions of this invention to the oral cavity whichcomprises

a) a confectionery composition; and

b) an effective amount of an active pharmaceutical composition dispersedwithin a water-in-oil emulsion system having at least two phases, onephase comprises from about 75 to about 99% by volume of an internalhydrophylic phase and the other phase comprises from about 25% to about1% by volume of an external hydrophobic phase, wherein the externalhydrophobic phase is comprised of two components, one component beingabout 3 to about 97% of a hydrophobic oil and the other being about 97%to about 3% of an emulsifier having a HLB value less than 10.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an orally useable emulsion or suspensionhaving varying viscosities and flow characteristics. Preferably thesystem is a liquid or semi-liquid emulsion or suspension system or asolid emulsion that liquifies at body temperatures to be taken orallyfor the purpose of coating the oral cavity, esophageal and/or GI tractmembranes. Alternatively the emulsion is delivered in a suitablepharmaceutical carrier, a chewing gum composition, a confectionerycomposition or other acceptable carrier vehicle.

When the emulsions are used either directly or with a carrier they areintended to remain in place for extended periods of time and can serveas a reservoir for the delivery of drug or pH modifying ingredients. Theproperty common to all formulations of this invention is the coating andadhering of the system to mucosal membranes of the mouth, pharynx,esophagus and/or GI tract for extended periods of time.

The formulations coat and protect membranes of the mouth, esophagusand/or GI tract against gastric fluid, and/or enzyme attack whilepromoting healing of esophagitis and ulcers as well as other disorders.The resulting protective layer also has the potential to provide areservoir of drugs or pH modifying ingredients.

The formulations may contain an extended release buffer for controllingpH over an extended period of time by prolonged residence throughadhesion to the esophagus and villi as well as through swelling andresisting pylorus dumping. In addition, the film layer, which isamorphous in structure when adhered to biological tissue, continuallyadjusts itself with organ musculature creating a symbiotic, therapeuticdelivery system residing for extended periods of time in the targettissue, such as in the mouth, esophagus, pharynx and/or stomach. Becauseof the unique emulsion system, the protective film has the potential toincrease in thickness as time goes on by absorption of resident fluidsinto the hydrophylic layer of the system. This can then provide athicker layer as a protectant. In contrast, prior art polymer systemshave the potential to wash away quickly.

As discussed, the bioadherent system of this invention is able to adhereto the mucosa for long periods of time. During adherence, the systemabsorbs moisture and enables the drug to be transported across theepithelial tissue. Adherence occurs for from 30 minutes to 24 hours andpreferably 2 to 8 hours. It has been calculated that by using the systemof this invention a diffusion matrix is formed which enables thetransport of biologically active material from the system through theepithelial tissue in less than 2 hours and preferably from 50 minutes to2 hours. While not being bound by any particular theory of activity, itis believed that the present bioadhesion system enables sufficientactive ingredient to diffuse from the bioadhesive substrate through theoral or esophageal epithelium and through and into the vasculature ofthe capillary beds present within the oral and esophageal mucosa. Thesecapillary beds have direct access to and are drained into the generalsystemic circulation of fluids within the body including plasma, serum,lymph and blood.

A distinct advantage of using a bioadhesive substrate on the oral andesophageal mucosa is to effect the systemic circulation of sufficientactive agents resulting from an oral administration of the activeagent/drug delivery system to the oral cavity and esophagus. In thismanner, biologically sensitive material may be administered orally,which has not been possible heretofore.

In conventional treatments, biologically sensitive material, such asproteins and hormones are administered by direct injection or infusiondirectly into the systemic circulation because the active drug isessentially digested and destroyed after introduction into thegastrointestinal tract. In the present bioadhesive delivery systems, theactive drug is delivered in a protected manner that is not hostile tothe active drug and, yet, due to the bioadhesive nature of the drugdelivery platform, allows sufficient retention time at the site ofabsorption for sufficient absorption of the active drug. Further,incorporation of the active drug in the bioadhesive delivery system isexpected to stabilize the active drug from both chemical and physicaldegradation.

The phrase "oral disorders" or "dental disorders," relates to disordersof the lips, mouth and tongue including buccal mucosa, salivary glands,palate and stomatitis; dental caries including pulpits and periapicalabscess; periodontal disease including gingivitis and periodontitis;temporomandibular joint disorders; neoplasms of tissue; and dentalemergencies including toothache, fractured and avulsed teeth, and soforth.

The phrase "pharynx, esophageal and/or GI tract disorders" relates tothose disorders found in the pharynx, esophagus, functional dyspepsiaand from other nonspecific gastrointestinal complaints, gastrointestinalbleeding, disorders of the esophagus, stomach, and duodenum, acuteabdomen and surgical gastroenterology, diarrhea and constipation,gastroenteritis, inflammatory diseases of the bowel and so forth.

Specific nonlimiting disorders that are treatable by the emulsions ofthis invention include the following:

Pre-esophageal dysphagia; esophageal dysphagia; gastroesophageal reflux;corrosive esophagitis and stricture such as

a) esophageal diverticula

b) hiatus hernia (or gastroesophageal reflux disease (GERD))

c) esophageal laceration and rupture, and

d) infectious disorders of the esophagus; functional dyspepsia; nauseaand vomiting; globus sensation; adult rumination; halitosis, real andimagined; arteriovenous malformations; gastritis; peptic ulcer;neoplasms of the stomach; abdominal pain; peritonitis; pancreatitis;cancer of the pancreas; diarrhea; constipation; gastroenteritis due tobacterial enterotoxins; hemorrhagic colitis; staphylococcal foodpoisoning; botulism; malabsorption syndromes such as

i) carbohydrate intolerance

ii) celiac disease

iii) tropical spruce

iv) whipple's disease

v) intestinal lymphangiectasia and

vi) infection and infestation; Crohn's disease; ulcerative colitis andso forth.

Besides treating these various disorders, the delivery system is usefulin enhancing the transport of biologically active components across theepithelium and into the capillary beds or circulatory structures withinthe epithelial mucosa. In this manner, biologically active materialwhich would be rendered inactive by stomach acids or stomach/intestinalenzymes are able to be administered orally without need for injection.Examples of useful compounds that may be administered in this mannerinclude proteins, peptides, polypeptides, hormones, and so forth.Non-limiting examples include the human growth hormone (hGH), insulin,tissue plasminogen activator (tPA), calcitonin, atrial natriureticfactor, and erythropoietin. The present system is composed of twophases; a hydrophylic inner phase and a hydrophobic external phase. Moreparticularly, the present system comprises a water-in-oil system havingat least two phases, one phase comprises from about 75 to about 99% byvolume of an internal hydrophylic phase and the other phase comprisesfrom about 25% to about 1% by volume of an external hydrophobic phase. Aunique feature of the external hydrophobic phase is that it is comprisedof two components, one component being about 3 to about 97% by volume ofthe hydrophobic phase of a hydrophobic oil and the other being about 97%to about 3% by volume of the hydrophobic phase of an emulsifier having aHLB value less than about 10.

The hydrophylic polymer phase is present in the delivery system inamounts of about 75% to about 99% and preferably about 80% to about 90%by volume of the overall system. As discussed above, the hydrophylicpolymer phase is present in amounts far greater than the externalhydrophobic phase and is situated to enable the retention of activematerial, when used.

Preferably the hydrophylic phase is selected from the group consistingof water, glycerine, sorbitol solutions, sugar syrups, polymer solutionsand mixtures thereof. The hydrophylic polymer material does not have tohave any solubility in the hydrophobic phase and is preferably selectedfrom water and sorbitol solutions, such as solutions containing 70% byvolume sorbitol. A variety of natural polymers or derivatives thereof aswell as synthetic polymers may also be used. Exemplary polymers includepolyethylene glycol polymers having mean average molecular weight of atleast 1000 and preferably from about 200 to 2 million or more. Exemplarysugar syrups include corn syrup, high fructose corn syrup and exemplarysugar solutions include cane sugar solutions, dextrose solutions,lycasin and so forth.

The hydrophobic phase is present in the delivery system in amounts farless than the internal phase. In general amounts of about 25% to about1% by volume of the system are useable with preferred amounts of about20% to about 10% being used. The hydrophobic phase is specificallydesigned to avoid the prior use of low amounts of emulsifier. Inparticular the present system is composed of two components, ahydrophobic oil and an emulsifier.

Generally amounts of hydrophobic oil of about 3% to about 97% are usedin the external system, based on the weight of the external system. Inaddition, amounts of about 3% to about 97% of the emulsifier are alsopresent in the external phase. By raising the emulsifier content in theexternal phase to be about or less than 50% of the oil phase, anadhesive formulation is prepared which will adhere to the GI tractmucosa lining. The configuration of the external phase is critical toprevent the internal phase for coalescing and disintegrating after use.By using relatively high levels of emulsifiers and blends thereof, thecapability of the internal phase to absorb aqueous components isenhanced.

The hydrophobic oil may be selected from a wide variety of materials,and is preferably a mineral oil, natural or synthetic vegetable oil,long chain fatty acids and alcohols of straight chain alkyls having from12 to 32 carbon atoms, waxes and mixtures thereof.

Any physiologically acceptable orally useable oil or mixtures thereofincluding those oils which satisfy the specifications of the UnitedStates Pharmacopeia or National Formulary may be utilized in thepractice of the invention. Representative members include peanut oil,safflower oil, soya bean oil, cottonseed oil, light mineral oil, cornoil, olive oil, sesame oil, almond oil, castor oil, isopropyl myristateand coconut oil. Of particular preference is mineral oil.

Particularly preferred wax materials are selected from animal waxes,vegetable waxes, petroleum waxes, synthetic waxes, and mixtures thereofand include without limitation beeswax, lanolin, candelilla wax,carnauba wax, microcrystalline wax, carbowax, and mixtures thereof.Furthermore, the wax material may be selected from the group consistingof lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid,linoleic acid, linolenic acid, and mixtures thereof.

The emulsifier used in the formulations of this invention find utilityfor preventing the internal phase from coalescing and disintegratingafter used. It has the advantage of increasing the efficacy of any drugused over that obtainable with commercial formulations. Anotherdesirable feature is that it is free of extraneous ionic materials thatmay be present in prior art preparations.

Preferably, the emulsifiers are soluble in the hydrophobic (lipoidal) orexternal phase. Suitable emulsifiers are those oil miscible surfaceactive compounds which are acceptable for use in foods, pharmaceuticals,and/or cosmetics Examples of such emulsifiers are low molecular weightpolyglycerols which have been esterified with fatty acids or fatty acidesters, or mono and diglyceride mixtures alone or with the addition ofmetallic soaps, such as, aluminum stearate. The metallic soaps appear toimprove the characteristics of some of the emulsions.

Particularly preferred emulsifiers have a HLB value less than about 10in order to obtain these desirable features. HLB is a qualitativedescription for emulsifiers wherein the ratio of hydrophile to lipophilecan be assessed. Emulsifiers with HLB's below 10 are more lipid solublethan water soluble and tend to form stable water-in-oil emulsions.

The emulsifier is preferably selected from sorbitan esters, polyglycerolesters of fatty acids, glycerol esters of fatty acids, 1 to 5 moleethoxylates of fatty acids or esters, saccharide derivatives andmixtures thereof. Particularly preferred emulsifiers are selected fromthe group consisting of polyglycerol oleate, sorbitan monooleate,glycerol monooleate and mixtures thereof.

Examples of saccharide derivatives include fatty acid saccharidederivatives such as sucrose oleate and sucrose stearate. Examples ofglycerol and polyglycerol esters include mono, di, tri and polyglycerolesters with oleic acid and stearic acid. The carbon chain length of thefatty acids may be from about C₁₀₋₂₂ and preferably is from aboutC₁₂₋₁₈.

In addition to the noted component parts of the hydrophobic layer, thislayer may also include other components to aid in the formation of thewater-in-oil emulsions of this invention. Such components may includediluents as well as other excipients; binders such as ethylcellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidone; and the like.

The formulations viscosities are prepared to have a liquid tosemi-liquid consistency, that is they may range from being pourable tohaving a semi-thick consistency. Solid emulsion formulations thatliquify at body temperature are also achievable and are desirable whereportability and ease of use by a patient are important. When using solidor semi-solid viscosities it is important that after the formulation istaken orally for it to start to exhibit a flow character to enablecoating of the pharynx, esophagus, and GI tract. Thicker materials donot coat well and remain as a bolus in the stomach. Thinner viscositiestend to flow too easily and do not coat uniformly and may pass throughthe GI tract too quickly. Preferably viscosity ranges of about 20,000 toover 1 million centipoise are effective herein. If the viscosities aretoo low, the emulsion destabilizes and comes apart, rendering theproduct unusable.

The overall degree of hardness, tack and melting point is controlledprimarily by the blending of the external phase components, and to alesser degree by the amount of dissolved species in the internal phase.A certain degree of plasticity is also required in the external phase,otherwise the finished product will crack and weep rather easily.Plasticity is usually achieved by incorporating appropriate amounts oflipid-soluble oils and liquid surfactants. The main types of ingredientsused to control the overall melting point and hardness are the hard fats(mostly triglycerides, but some mono and diglycerides), waxes (paraffin,microcrystalline, vegetable, mineral and animal), fatty alcohols andacids and fatty acid esters. These techniques are well known informulating solids compositions that melt at body temperature.

The formulations of the invention may be used as is when preblended withan active material or drug when being prepared. While not being limitedthereto, water-soluble drugs are preferably used in the hydrophylicinternal phase whereas water-insoluble drugs are present in the externalhydrophobic phase.

The active material(s) or drug(s) may be described as a single drugentity or a combination of

Anti-pyretic and analgesic agents

Anti-spasmodic agents

Anti-thrombotic agents

Anti-uricemic agents

Antihistamines

Antitussives

Appetite suppressants

Biologicals

Cerebral dilators

Coronary dilators

Decongestants

Diuretics

Erythropoietic agents

Expectorants

Gastrointestinal sedatives

Hyper-glycemic agents

Hypnotics

Hypo-glycemic agents

Ion exchange resins

Laxatives

Mineral supplements

Mucolytic agents

Neuromuscular drugs

Peripheral vasodilators

Psychotropics

Sedatives

Stimulants

Thyroid and anti-thyroid agents

Uterine relaxants

Illustrative categories and specific examples of active drugs include:(a) antitussives, such as dextromethorphan, dextromethorphanhydrobromide, noscapine, carbetapentane citrate, and chlophedianolhydrochloride; (b) antihistamines, such as chlorpheniramine maleate,phenindamine tartrate, pyrilamine maleate, doxylamine succinate, andphenyltoloxamine citrate; (c) decongestants, such as phenylephrinehydrochloride, phenylpropanolamine hydrochloride, pseudoephedrinehydrochloride, ephedrine; (d) various alkaloids, such as codeinephosphate, codeine sulfate and morphine; (e) mineral supplements such aspotassium chloride, zinc chloride and calcium carbonates, magnesiumoxide and other alkali metal and alkaline earth metal salts; (f)laxatives, vitamins and antacids (g) ion exchange resins such ascholestryramine; (h) anti-cholesterolemic and anti-lipid agents; (i)antiarrhythmics such as N-acetylprocainamide; (j) antipyretics andanalgesics such as acetaminophen, aspirin and ibuprofen; (k) appetitesuppressants such as phenylpropanolamine hydrochloride or caffeine; and(l) expectorants such as guaifenesin; (m) antacids such as aluminumhydroxide and magnesium hydroxide, (n) biologicals such as peptides,polypeptides, proteins and amino acids, hormones, vaccines, fragmentdrugs such as growth hormones, interferons and other bioactivepeptididic compounds, such as HGH, TPA, calcitonin, ANF, EPO andinsulin, and (o) anti-infective agents such as antifungals, antivirals,antiseptics and antibiotics.

Additional useful active medicaments include anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, anti-infectives, psychotropics, antimanics, stimulants,laxatives, gastrointestinal sedatives, antidiarrheal preparations,antianginal drugs, anticoagulants and antithrombotic drugs, hypnotics,sedatives, anti-emetics, anti-nauseants, anticonvulsants, neuromusculardrugs, hyper- and hypo-glycemic agents, thyroid and antithyroidpreparations, diuretics, antispasmodics, uterine relaxants, antiobesitydrugs, anabolic drugs, erythropoietic drugs, antiasthmatics, coughsuppressants (anti-tussives), mucolytics, anti-uricemic drugs, and thelike.

The drugs are used in amounts that are therapeutically effective. Whilethe effective amount of a drug will depend on the drug used, amounts ofdrug from about 5% to about 65% have been easily incorporated into thepresent delivery systems while achieving controlled release.

The systems may be prepared by continuous or batch processes. As inpreparing conventional emulsions, shear force is applied to the systemcomponents by use of homogenizers, mills, impingement surfaces,ultra-sound, shaking or vibration. Unlike conventional emulsions, themixing shear should be at low levels in order to prevent destruction ofthe system by imparting excess energy. Temperature is not usually acritical factor in the preparation of the systems. The temperaturesutilized will be dependent upon the final end product desired.

The systems may be prepared by mixing the internal with the externalphase in a planetary-type mixer. Another manner of preparing the systemis by use of a continuous mixer which comprises multiple impellers. Theexternal phase is first introduced into the continuous mixer until itreaches the level of the lowest impeller in the mixing chamber. The twophases are then simultaneously introduced through the bottom of themixer in proper proportion as its impeller or impellers rotate to applya shear to the components. The finished product emerges through the topof the mixer. The actual speed of the impeller or impellers will vary,depending upon the product produced as will the rate of flow of the twophase streams.

In a preferred embodiment, the active agent or drug and ingredients ofthe internal phase were mixed together at room temperature (24° C.). Theingredients of the external phase were mixed together in a separatevessel. The internal phase composition was slowly added to the externalphase composition as the two phases are mixed together at low shearuntil the desired viscosity was obtained.

Generally, the emulsions are prepared by separately making thehydrophylic and hydrophobic phases and then blending the phases togetherby adding the hydrophylic phase to the hydrophobic phase. In aparticularly preferred procedure the hydrophobic phase is prepared byblending the hydrophobic oil together with the emulsifier material. Thehydrophylic phase is then added in incremental amounts to thehydrophobic phase while mixing the components. As more and more of theaqueous phase is added the product begins to thicken. When the phasecombination is complete, the product can be pumped, or filled into afinal pharmaceutically acceptable carrier.

The emulsion once prepared may be stored for future use or formulatedwith conventional additives, that is pharmaceutically acceptablecompounds and/or carriers, to prepare compositions which offer a varietyof textures to suit particular applications. Such compositions may be inthe form of a lozenge, tablet, toffee, nougat, chewy candy, oral hygienepreparations, breath fresheners, chewing gum, and other oralformulations.

The preparation of confectionery and chewing gum products is well known.When used in such delivery systems, the formulations of this inventionmay be blended with the confectionery or chewing gum product, coated onthe surface thereof or even center filled to enable the active componentto be administered.

As used herein, the term confectionery material means a productcontaining a bulking agent selected from a wide variety of materialssuch as sugar, corn syrup and in the case of sugarless bulking agentssugar, corn syrup and in the case of sugarless bulking agents sugaralcohols such as sorbitol and mannitol and mixtures thereof.Confectionery material may include such exemplary substances aslozenges, tablets, toffee, nougat, chewy candy and so forth. In general,the bulking agent will comprise from about 5 to about 99% and preferably20 to about 95% by weight of the medicated confectionery product.

Lozenges are flavored medicated dosage forms intended to be sucked andheld in the mouth. They may be in the form of various shapes, the mostcommon being flat, circular, octagonal and biconvex forms. The lozengebases are generally in two forms, hard, boiled candy lozenges andcompressed tablet lozenges.

The hard boiled candy lozenges are prepared from a mixture of sugar andother carbohydrates that are kept in an amorphous or glassy condition.This form can be considered a solid syrup of sugars generally havingfrom 0.5 to about 1.5% moisture. Such materials normally contain up toabout 92% corn syrup, up to about 70% sugar and from 0.1% to about 5.0%water. The syrup component generally is prepared from corn syrups highin dextrose, but may include other materials. Further ingredients suchas flavorings, sweeteners, acidulents, colorants and so forth may alsobe added.

Boiled candy lozenges may also be prepared from nonfermentable sugarssuch as sorbitol, mannitol and hydrogenated corn syrup. The candylozenges may contain up to about 95% sorbitol, a mixture of sorbitol andmannitol at a ratio of about 9.5 to 0.5 up to about 7.5 to 2.5 andhydrogenated corn syrup up to about 55% of the syrup component.

In contrast, compressed tablet lozenges contain particular materials andare formed into structures under pressure. They generally contain sugarsin amounts up to 95% and typical tablet excipients such as binders andlubricants as well as flavors, colorants and so forth.

The lozenges may be made of soft confectionery materials such as thosecontained in nougat. These materials contain two primary components,namely a high boiling syrup such as corn syrup or the like, and arelatively light textured frappe, generally prepared from gelatin, eggalbumen, milk proteins such as casein, and vegetable proteins such assoy protein and the like. The frappe is generally relatively light, andmay, for example, range in density from about 0.5 to about 0.7 g/cc.

By comparison, the high boiling syrup, or "bob syrup," is relativelyviscous and possesses a higher density and frequently contains asubstantial amount of sugar. Conventionally, the final nougatcomposition is prepared by the addition of the "bob syrup" to the frappeunder agitation, to form the basic nougat mixture. Further ingredientssuch as flavorings, oils, additional sugar and the like may be addedthereafter also under agitation. A general discussion of the compositionand preparation of nougat confections may be found in B. W. Minifie,CHOCOLATE, COCOA AND CONFECTIONERY: Science and Technology, 2nd edition,AVI Publishing Co., Inc., Westport, Conn., (1980), at 15 pages 424-425,which discloses is incorporated herein by reference.

Unlike lozenges, nougat formulations are prepared by admixing the nougatcandy base with the remaining ingredients, including active formulationsof this invention, until a homogenous admixture is obtained and thenforming the resulting mixture into suitable shapes for storage. Thepreparation of the nougat candy base may be achieved by routineprocedures well known to the ordinary skilled artisan. One preferredprocedure involves the preparation of a whipping component and blendingwith it a syrup component. See, for example U.S. Pat. No. 4,683,138 toGlass et al.

The whipped component may be prepared by mixing the whipping agent withother desirable components. The whipped component is generally preparedfrom gelatin, egg albumen, milk proteins such as casein, and vegetableproteins such as soy protein, and the like which are added to a gelatinsolution and rapidly mixed at ambient temperature to form an aeratedsponge like mass.

The syrup component is prepared by initially mixing corn syrup, sugarcomponent and an amount of water necessary to assure solution of theingredients. The total water content is not critical, however, it ispreferable to keep the initial water content below 40% by weight. Thismixture is charged into a suitable cooker and cooked to a final watercontent of about 2% to about 11.0% by weight.

Once the above steps are complete, the whipped component and the syrupcomponent may be combined, usually by the addition of whipped componentto the syrup component after the syrup component's temperature hasdropped to about 110° C. to about 118° C. The resultant combination isthen mixed. At this point, an edible polyol may be added. If colorantsare to be incorporated, they may be incorporated into the candy base atthis point. The composition is then mixed until a uniform homogenousmass is formed.

The emulsions of this invention may then be added and mixed until auniform homogenous mass is formed. If fats are to be incorporated, theyare incorporated into the candy base at this time. The above compositionis mixed until the temperature of the composition is less than about 90°C. but greater than about 60° C. At this point, a graining compound, ifemployed, is added to the composition. If flavorings are to beincorporated, they may be added into the candy base also at this time.The mixture is then further mixed until uniform.

One or all of the reagents have been blended into the mixture, themixture allowed to cool. The mixture may be cooled to ambienttemperatures before final forming operations are completed.

A variety of final forming techniques may be utilized, depending uponthe shape and size of the final product as desired.

Once prepared the final composition may be processed into any desirableshape or form to render the product suitable for providing the necessaryamount of active compound. Exemplary, non-limiting shapes includesquares, rectangles, spheres, tabloids and biconvex shapes. Othersuitable shapes may also be employed.

In the practice of this invention, any conventional chewing gumcomposition of the prior art may be used to assist in the delivery ofthe emulsions of this invention. The emulsions may be blended in thechewing gum composition, serve as a coating layer thereon or even becenter-filled within the chewing gum composition.

Without being limited to specific chewing gum formulations, exemplaryexamples are described in U.S. Pat. Nos. 4,775,537 and 4,683,138. Theseformulations generally contain a gum base and modifiers to form anacceptable texture and sweetness.

The gum base compositions may contain conventional elastomer solvents toaid in softening the rubber component. Such elastomer solvents maycomprise methyl, glycerol or pentaerythritol esters of rosins ormodified rosins, such as hydrogenated, dimerized or polymerized rosinsor mixtures thereof. Examples of elastomer solvents suitable for useherein include pentaerythritol ester of partially hydrogenated wood orgum rosin, pentaerythritol ester of wood or gum rosin, glycerol ester ofpartially dimerized rosin, glycerol ester of polymerized rosin, glycerolester of tall oil rosin, glycerol ester of wood or gum rosin andpartially hydrogenated wood or gum rosin, and partially hydrogenatedwood or gum rosin, and partially hydrogenated methyl ester of rosin andmixtures thereof. The elastomer solvent may be employed in an amountranging from about 10% to about 75% and preferably about 45% to about70% by weight of the gum base.

A variety of traditional ingredients used as plasticizers or softenerssuch as lanolin, stearic acid, sodium stearate, potassium stearate,glycerol triacetate, glycerin, lecithin, and glycerol monostearate andthe like, may also be incorporated into the gum base to obtain a varietyof desirable textures and consistency properties. These additionalmaterials are generally employed in amounts up to about 30% by weightand preferably in amounts of from about 3% to about 5% by weight of thefinal gum base composition.

The chewing gum compositions may also employ sweetening agents(sweeteners). The sweetening agent may be selected from a wide range ofmaterials including water-soluble sweetening agents, water-solubleartificial sweeteners, water-soluble sweetening agents derived fromnaturally occurring water-soluble sweeteners, dipeptide basedsweeteners, and protein based sweeteners, including mixtures thereof.

The chewing gum compositions may additionally include effective amountsof the conventional additives of coloring agents such as titaniumdioxide; emulsifiers such as lecithin and glycerol monostearate;maltodextrins; and fillers such as aluminum hydroxide, alumina, aluminumsilicates, talc, dicalcium phosphate, calcium carbonate, andcombinations thereof. Preferably the amount of fillers used is up toabout 25% by weight of the gum base.

The chewing gum compositions may be produced by techniques well known tothose skilled in the art. For example, using conventional equipment thegum base is heated to temperatures sufficiently high enough to softenthe base without adversely effecting the physical and chemical make upof the base. The optimum temperatures utilized may vary depending on thecomposition of the gum base used, but such temperatures are readilydetermined by those skilled in the art without undue experimentation.For example, suitable temperatures for softening the gum base are withinthe range of about 70° C. to about 90° C. Temperatures within the rangeof about 40° C. to about 60° C. may be used with the gum basecompositions disclosed in, for example U.S. Pat. No. 4,587,125. Duringheating, the gum base is mixed with any of the optional componentstraditionally used with the gum base, such as plasticizers and elastomersolvents. In general, the order of addition of the various components(ingredients) of the chewing gum composition is not critical. Theflavoring agents, however, should be added when the gum base has beenallowed to cool to a temperature below the volatilization temperature ofthe flavoring agents used. The flavors may be added separately orblended together as a preblend before their addition. The mixture soproduced is then extruded, using conventional equipment, and formed intosuitable chewing gum shapes. The emulsions of this invention may beadded during the formation of the gum product or after it is formedeither before or after the flavors are blended in the chewing gumcomposition.

Regarding center filled gum, the emulsions of this invention may bepumped into a center-fill through a hollow-centered rope of chewing gumwhich is then cut into pieces. The center-filled emulsion is thenreleased upon chewing the gum composition resulting in release of theemulsion into the oral cavity.

The pharmaceutically acceptable carriers may be prepared from a widerange of materials. Without being limited thereto, such materialsinclude diluents, binders and adhesives, lubricants, disintegrants,colorants, bulking agents, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated composition.

It is believed that the release mechanism of active components may be acombination of several phenomena once the formulation is adhered to theGI tract. Enzymatic degradation of the system, diffusion of the drugthrough the system, competitive adsorption, desorption of hydrophobiccomponents from hydrophylic surface centers, convection of the drugthrough mesopores and macropores, diffusion of the external medium intothe system by way of solubility or capillary action through porousstructures created by the addition of hydrophylic polymers orwater-soluble solids, as well as expansion of drug and/or system fromwater absorption into the inner phase.

The term pharmaceutically acceptable carriers as used herein meansubstances and materials generally used in the drug or food industrywhich do not alter the basic character and function of the activecomponent or oral delivery system.

Flavors which may optionally be added to the delivery system are thosewell known in the pharmaceutical art. For example, synthetic flavoroils, and/or oils from plants, leaves, flowers, fruits and so forth, andcombinations thereof are useful.

Representative flavor oils include spearmint oil, peppermint oil,cinnamon oil, and oil of wintergreen (methylsalicylate). Also useful areartificial, natural or synthetic fruit flavors such as citrus oilsincluding lemon, orange, grape, line and grapefruit, and fruit essencesincluding apple, strawberry, cherry, pineapple, and so forth.

The amount of flavoring agent employed is normally a matter ofpreference subject to such factors as flavor type, base type andstrength desired. In general, amounts of about 0.05% to about 25.0% byweight of the final product are useful with amounts of about 0.3% toabout 1.0% being preferred and about 0.8% to about 8% being mostpreferred.

The delivery system may contain a sweetening agent. Sweetening agentsmay be selected from a wide range of materials such as water-solublesweetening agents, water-soluble artificial sweeteners, and dipeptidebased sweeteners, including mixtures thereof. Without being limited toparticular sweeteners, representative illustrations encompass:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, sugar, maltose,partially hydrolyzed starch, or corn syrup solids and sugar alcoholssuch as sorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium or calcium saccharin salts, cyclamate salts,acesulfam-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-aspartyl L-phenylalanine methylester and materials described in U.S. Pat. No. 3,492,131 and the like.

Representative examples of other conventional additives include thefollowing nonlimiting materials:

(a) Preservatives such as benzoic acid, sorbic acid, methylparaben,propylparaben and ethylenediaminetetraacetic acid (EDTA). Preservativesare generally present in amounts up to about 1% and preferably fromabout 0.05 to about 0.5% by weight of the suspension;

(b) Buffers such as citric acid-sodium citrate, phosphoric acid-sodiumphosphate, and acetic acid-sodium acetate in amounts up to about 1% andpreferably from about 0.05 to about 0.5% by weight of the suspension;

(c) Suspending agents or thickeners such as cellulosics likemethylcellulose, carageenans like alginic acid and its derivatives,xanthan gums, gelatin, acacia, and microcrystalline cellulose in amountsup to about 20% and preferably from about 1% to about 15% by weight ofthe suspension;

(d) Antifoaming agents such as dimethyl polysiloxane in amounts up toabout 0.2% and preferably from about 0.01 to about 0.1% by weight of thesuspension;

(e) Colorants useful in the present invention include pigments which maybe incorporated in amounts of up to about 5 by weight of thecomposition. A preferred pigment, titanium dioxide, may be incorporatedin amounts up to about 1%. Also, the colorants may include other dyessuitable for food, drug and cosmetic applications, and known as F.D.&C.dyes and the like. Such dyes are generally present in amounts up toabout 0.25% and preferably from about 0.05% to about 0.2% by weight ofthe suspension;

(f) Decolorizing agents such as sodium metabisulfite, ascorbic acid andthe like may be incorporated into the suspension to prevent colorchanges due to aging. In general, amounts up to about 0.251% andpreferably 0.05% to 0.2% by weight of the suspension are used; and

(g) Solubilizers such as alcohol, propylene glycol, polyethylene glycoland the like may be used to solubilize the flavors. Solubilizing agentsare generally present in amounts up to 10%; preferably from about 2% toabout 5% by weight of the suspension.

While delivery systems based on the instant invention are generallyliquid, semi-liquid, and solid it is contemplated that they may beemployed, with or without the conventional supplemental agents, asprincipal components of systems to be dissolved or dispersed in water orother ingestible liquids for ingestion in a drinkable form.

The additives are added to the oral delivery system anytime duringprocessing. It should be recognized that certain additives should beadded prior to, during or after the active material is blended into thesystem in order to achieve uniform distribution of the ingredients.Preferably, additives in liquid form are added before the activematerial whereas powdered additives may be added before or after theactive material is added.

The formulations may also be formulated with conventional well knowningredients to form lip balm or components of lip stick to aid indelivery of the active drug present in the emulsion.

The following examples are illustrative of preferred embodiments of theinvention and are not to be construed as limiting the invention thereto.All percentages are based on the percent by weight of the deliverysystem unless otherwise indicated and all totals equal 100% by weight.

EXAMPLE 1

This example describes the preparation of a long acting GI tract andesophageal protectant.

In separate vessels the internal phase and external phases were preparedwith the components identified below. Once prepared the internal phasewas added incrementally to the external phase while blending themixture.

The internal phase may be prepared by placing the water into containersand heating to 70°-80° C. The sorbitol is then added and the systemmixed to form a homogenous mixture. The parabens are then added andmixed until they are dissolved (about 15 minutes) The system is thencooled to about 35° C. or less.

The external phase is prepared by blending the oil and polyglyceroltogether, such as in a blender, for about 15 minutes.

The emulsion is then formed by adding the internal phase to the externalphase while mixing. Mixing is continued for several minutes to form astable emulsion.

    ______________________________________                   Wt %    ______________________________________    Internal Phase    Water            72.8    Sorbitol 70      8.0    Methylparaben    0.13    Propylparaben    0.07    External Phase    Mineral Oil      10.0    Polyglycerol Oleate                     9.0    ______________________________________

EXAMPLE 2

This example describes the preparation of a long acting GI tract andesophageal protectant with an antacid compound added to the internalphase.

In separate vessels the internal phase and external phases were preparedwith the components identified below according to the procedure setforth in Example 1.

The internal phase was prepared by putting the glycerin into a vesseland warming it to 70°-80° C. The methyl and propyl parabens are thenadded and stirred until they dissolve (about 10 minutes). While stirringadd the potassium sodium tartrate with Mg (OH)₂ and Al (OH)₃ to themixture at about 40° C. Add sucrose and stir until it dissolves, about10 minutes.

    ______________________________________                     Wt %    ______________________________________    Internal Phase    Glycerin           22.99    Methylparaben      0.1    Propylparaben      0.01    Potassium sodium tartrate                       0.9    Mg(OH) 3.7% potassium                       14.0    Al(OH).sub.3 gel   28    Sucrose            15.0    External Phase    Mineral Oil        10.0    Polyglycerol Oleate                       9.0    ______________________________________

EXAMPLE 3

The oral preparation of Example 2 could be used for the antacid ifreplaced with human growth hormone wherein the hormone was added to theinner phase (Step 1) in amounts of about 0.01% to about 2.0% by weight.Human growth hormone is a single poly-peptide chain of 191 amino acidshaving a molecular weight of 22,124, having the empirical formulation ofC₉₉₀ H₁₅₂₉ N₂₆₃ O₂₉₉ S₇, also known as HGH, somatotropin and humangrowth hormone. When consumed orally, the preparation would be expectedto adhere to the oral and esophageal mucosa for 2 to 8 hours withdiffusion of the drug being completed within the first two hours of use.

EXAMPLE 4

The procedure of Example 3 could be repeated with 0.01% to 2.0% tissueplasminogen activator. TPA, also known as fibrinokinase, molecularweight approximately 70,000, described as a peptiditic human therapeuticagent used to prevent the formation of fibrin clots or dissolve fibrinclots. When consumed orally, the preparation would be expected to adhereto the oral and esophageal mucosa for 2 to 8 hours with diffusion of thedrug being completed within the first two hours of use.

EXAMPLE 5

The procedure of Example 3 could be repeated with 0.00001% to 0.1%calcitonin added to the base delivery system. Calcitonin, also known asthyrocalcitonin, or TCA, molecular weight approximately 4,500, is anaturally occurring hormone secreted from mammalian thyroid gland. Whenconsumed orally, the preparation would be expected to adhere to the oraland esophageal mucosa for 2 to 8 hours with diffusion of the drug beingcompleted within the first two hours of use.

EXAMPLE 6

The procedure of Example 3 could be repeated with 0.0001% to 0.1% ANFadded to the base delivery system. Atrial natriuretic factor, also knownas atriopeptin, or ANF, is a potent peptide or mixture of homologouspeptides derived from the atrium of mammalian heart and is involved inthe hormonal regulation of fluid volume and blood pressure. ANF iscomposed of 21-33 specific amino acids having a molecular weight ofapproximately 4,000. When consumed orally, the preparation would beexpected to adhere to the oral and esophageal mucosa for 2 to 8 hourswith diffusion of the drug being completed within the first two hours ofuse.

EXAMPLE 7

The procedure of Example 3 could be repeated with 0.001% to 0.1%Erythropoietin added to the base delivery system. Erythropoietin, alsoknown as erythropoiesis stimulating factor, EPO, or epogen, is aglycoprotein which stimulates red blood cell formation, produced mainlyin the kidneys of mammals, and has been recently produced by geneticengineering. When consumed orally, the preparation would be expected toadhere to the oral and esophageal mucosa for 2 to 8 hours with diffusionof the drug being completed within the first two hours of use.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A medicated chewing gum composition, whichcomprises:a) a gum base in an amount sufficient to form a chewing gumcomposition; b) effective amounts of chewing gum additives to soften thegum base; and c) an effective amount of an active pharmaceuticalcomposition dispersed within a water-in-oil emulsion system having atleast two phases, one phase comprises from about 75 to about 99% byvolume of an internal hydrophylic phase and the other phase comprisesfrom about 25% to about 1% by volume of an external hydrophobic phase,wherein the external hydrophobic phase is comprised of two components,one component being about 3 to about 97% of a hydrophobic oil and theother being about 97% to about 3% of an emulsifier having a HLB valueless than
 10. 2. The chewing gum composition of claim 1, wherein thehydrophylic phase contains an active pharmaceutical material.
 3. Thechewing gum composition of claim 2, wherein the active pharmaceuticalmaterial is water-soluble.
 4. The chewing gum composition of claim 1,wherein the hydrophylic phase is selected from the group consisting ofwater, glycerine, sorbitol solutions, sugar syrups, polymer solutionsand mixtures thereof.
 5. The chewing gum composition of claim 1, whereinthe phase is in the form of an emulsion or suspension.
 6. The chewinggum composition of claim 1, wherein the internal phase is present inamounts of about 80 to about 90% by volume.
 7. The chewing gumcomposition of claim 1, wherein the external phase contains an activepharmaceutical material.
 8. The chewing gum composition of claim 7,wherein the active pharmaceutical material is water-insoluble.
 9. Thechewing gum composition of claim 1, wherein the hydrophobic oil isselected from the group consisting of mineral oil, natural or syntheticvegetable oil, long chain fatty acids and alcohols of straight chainalkyls having from 12 to 32 carbon atoms, waxes and mixtures thereof.10. The chewing gum composition of claim 1, wherein the emulsifierpresent in the hydrophobic phase is selected from the group consistingof sorbitan esters, polyglycerol esters of fatty acids, glycerol estersof fatty acids, 1 to 5 mole ethoxylates of fatty acids or esters,saccharides derivatives and mixtures thereof.
 11. The chewing gumcomposition of claim 10, wherein the emulsifier is selected from thegroup consisting of polyglycerol oleate, sorbitan monooleate, glycerolmonooleate and mixtures thereof.
 12. The chewing gum composition ofclaim 1, wherein the external phase is present in amounts of about 20%to about 10% by volume of the entire system.
 13. The chewing gumcomposition of claim 9, wherein the wax is selected from the groupconsisting of animal waxes, vegetable waxes, synthetic waxes andmixtures thereof.
 14. The chewing gum composition of claim 7, whereinthe emulsion is center-filled within the chewing gum composition. 15.The chewing gum composition of claim 7, wherein the emulsion ishomogeneously mixed throughout the chewing gum composition.
 16. Amedicated confectionery composition, which comprises:a) a confectionerycomposition; and b) an effective amount of an active pharmaceuticalcomposition dispersed with a water-in-oil emulsion system having atleast two phases, one phase comprises from about 75 to about 99% byvolume of an internal hydrophylic phase and the other phase comprisesfrom about 25% to about 1% by volume of an external hydrophobic phase,wherein the external hydrophobic phase is comprised of two components,one component being about 3 to about 97% of a hydrophobic oil and theother being about 97% to about 3% of an emulsifier having a HLB valueless than
 10. 17. The confectionery composition of claim 16, wherein thehydrophylic phase contains an active pharmaceutical material.
 18. Theconfectionery composition of claim 17, wherein the active pharmaceuticalmaterial is water-soluble.
 19. The confectionery composition of claim16, wherein the hydrophylic phase is selected from the group consistingof water, glycerine, sorbitol solutions, sugar syrups, polymer solutionsand mixtures thereof.
 20. The confectionery composition of claim 16,wherein the phase is in the form of an emulsion or suspension.
 21. Theconfectionery composition of claim 16, wherein the internal phase ispresent in amounts of about 80 to about 90% by volume.
 22. Theconfectionery composition of claim 16, wherein the external phasecontains an active pharmaceutical material.
 23. The confectionerycomposition of claim 22, wherein the active pharmaceutical material iswater-insoluble.
 24. The confectionery composition of claim 16, whereinthe hydrophobic oil is selected from the group consisting of mineraloil, natural or synthetic vegetable oil, long chain fatty acids andalcohols of straight chain alkyls having from 12 to 32 carbon atoms,waxes and mixtures thereof.
 25. The confectionery composition of claim16, wherein the emulsifier present in the hydrophobic phase is selectedfrom the group consisting of sorbitan esters, polyglycerol esters offatty acids, glycerol esters of fatty acids, 1 to 5 mole ethoxylates offatty acids or esters, saccharides derivatives and mixtures thereof. 26.The confectionery composition of claim 25, wherein the emulsifier isselected from the group consisting of polyglycerol oleate, sorbitanmonooleate, glycerol monooleate and mixtures thereof.
 27. Theconfectionery composition of claim 16, wherein the external phase ispresent in amounts of about 20% to about 10% by volume of the entiresystem.
 28. The confectionery composition of claim 24, wherein the waxis selected from the group consisting of animal waxes, vegetable waxes,synthetic waxes and mixtures thereof.
 29. The confectionery compositionof claim 16, wherein the active pharmaceutical composition dispersedwithin the emulsion is coating on the surface of the confectionerycomposition.
 30. The confectionery composition of claim 16, wherein theemulsion is center-filled within the confectionery composition.
 31. Theconfectionery composition of claim 16, wherein the emulsion ishomogeneously mixed throughout the confectionery composition.